Pulmonary fungal infections are major causes of morbidity and mortality in immunocompromised patients. The immune system of an individual may be compromised by some diseases, such as acquired immunodeficiency syndrome (AIDS), and/or may be deliberately compromised by immunosuppressive therapy. Immunosuppressive therapy is often administered to patients undergoing cancer treatments and/or patients undergoing a transplant procedure. Immunocompromised patients have an increased susceptibility to pulmonary and/or nasal fungal infections. Severely immunocompromised patients, such as those with prolonged neutropenia or patients requiring 21 or more consecutive days of prednisone at doses of at least 1 mg/kg/day in addition to their other immunosuppressants, are particularly susceptible to pulmonary and/or nasal fungal infection. Among immunocompromised patients, overall fungal infection rates range from 0.5 to 28%. Of the autopsied bone marrow transplant patients with idiopathic pneumonia syndrome (IPS) at the Fred Hutchinson Cancer Center, 7.3% had IFPFI. In another study by Vogeser et al, a 4% rate of IFPFI was found in 1187 consecutive autopsies in European patients dying of any cause during the period from 1993 to 1996. An overwhelming majority of these European patients had received (1) high dose steroid doses; (2) treatment for a malignancy; (3) a solid organ transplant; or (4) some form of bone marrow transplant.
The most common pulmonary and/or nasal fungal infection in immunocompromised patients is pulmonary and/or nasal aspergillosis. Aspergillosis is a disease caused by Aspergillus fungal species (Aspergillus spp.), which invade the body primarily through the lungs. The incidence of aspergillosis depends on duration and depth of neutropenia, patient factors (e.g., age, corticosteroid use, and prior pulmonary and/or nasal disease), levels of environmental contamination, criteria for diagnosis, and persistence in determining the cause of the disease.
Other filamentous and dimorphic fungi can lead to pulmonary fungal infections as well. These additional fungi are usually endemic and regional and may include, for example, blastomycosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, and sporotrichosis. Though typically not affecting the pulmonary system, infections caused by Candida spp., which are usually systemic and most often result from infections via an indwelling device or IV catheter, wound, or a contaminated solid organ transplant, account for 50 to 67% of total fungal infections in immunocompromised patients.
Amphotericin B is the only approved fungicidal compound currently used to treat aspergillosis and is generally delivered intravenously. Amphotericin B is an amphoteric polyene macrolide obtained from a strain of Streptomyces nodosus. In its commercial form, amphotericin B is present in both amorphous and crystalline forms. Amphotericin B formulated with sodium deoxycholate was the first parental amphotericin B preparation to be marketed. Systemic intravenous therapies are constrained by dose-dependent toxicities, such as renal toxicity and hepatotoxicity, which hamper the effectiveness of the treatment and lessen the desirability of prophylactic use of amphotericin B. Even with the approved therapy, aspergillosis incidence is rising and estimated to cause mortality in more than 50% of those infected who receive treatment.
Other conditions and/or diseases may benefit from treatment according to one or more embodiments of the compositions and/or methods and/or systems of the present invention. In some embodiments, the conditions and/or diseases are those which primarily or initially affect the pulmonary system. For example patients with asthma, COPD and other sensitive lung conditions may be treated thereby. In other embodiments, the conditions and/or diseases are systemic, and pulmonary administration provides a safe and effective mode of administration. For example patients with AIDS (particularly late stage with neutropenia), genetic diseases and conditions, aplastic anemia, bone marrow transplants, organ transplants and leukemias, may be treated thereby. Thus the present invention provides for the prevention of fungal infections in patients at risk for aspergillosis due to immunosuppressive therapy including those receiving organ or stem cell transplants, or treated with chemotherapy or radiation for hematologic malignancies.
There remains a need in the art for safe and effective amphotericin B compositions, methods of making and using such compositions, and systems for using such compositions. For example, there remains a need for compositions and methods to safely and effectively treat patients who have developed a pulmonary and/or nasal fungal infection and/or provide prophylaxis against the onset of a pulmonary and/or nasal fungal infection. Moreover, there remains a need to safely and efficiently deliver effective doses of an antifungal composition, in particular an Amphotericin B composition, directly to the affected sites, such as to the lungs and/or nasal mucosa.